The present invention relates to compounds having agonist, partial agonist and antagonist activity for retinoid X receptors, and to methods for the production and therapeutic use of such compounds.
The vitamin A metabolite, retinoic acid, has long been recognized to induce a broad spectrum of biological effects. For example, retinoic acid-containing products, such as Retin-A(copyright) and Accutane(copyright), have found utility as therapeutic agents for the treatment of various pathological conditions. In addition, a variety of structural analogues of retinoic acid have been synthesized that also have been found to be bioactive. Many of these synthetic retinoids have been found to mimic many of the pharmacological actions of retinoic acid, and thus have therapeutic potential for the treatment of number disease states.
Medical professionals have become very interested in the therapeutic applications of retinoids. Among their uses approved by the FDA is the treatment of severe forms of acne and psoriasis. A large body of evidence also exists that these compounds can be used to arrest and, to an extent, reverse the effects of skin damage arising from prolonged exposure to the sun. Other evidence exists that these compounds have clear effects on cellular proliferation, differentiation and programmed cell death (apoptosis), and thus, may be useful in the treatment and prevention of a variety of cancerous and pre-cancerous conditions, such as acute promyleocytic leukemia (APL), epthelial cancers, squamous cell carcinomas, including cervical and skin cancers and renal cell carcinoma. Furthermore, retinoids may have beneficial activity in treating and preventing diseases of the eye, cardiovascular disease and other skin disorders.
Major insight into the molecular mechanism of retinoic acid signal transduction was gained in 1988, when a member of the steriod/thyroid hormone intracellular receptor superfamily was shown to transduce a retinoic acid signal. Giguere et al., Nature, 330:624-29 (1987); Petkovich et al., Nature, 330: 444-50 (1987); for review. See Evans, Science, 240:889-95 (1988). It is now known that retinoids regulate the activity of two distinct intracellular receptor subfamilies; the Retinoic Acid Receptors (RARs) and the Retinoid X Receptors (RXRs), including their subtypes, RARxcex1, xcex2, xcex3 and RXRxcex1, xcex2, xcex3. All-trans-retinoic acid (ATRA) is an endogenous low-molecular-weight ligand which modulates the transcriptional activity of the RARs, while 9-cis retinoic acid (9-cis) is the endogenous ligand for the RXRs. Heyman et al., Cell, 68:397-406 (1992) and Levin et al. Nature, 355:359-61 (1992).
Although both the RARs and RXRs respond to ATRA in vivo, due to the in vivo conversion of some of the ATRA to 9-cis, the receptors differ in several important aspects. First, the RARs and RXRs are significantly divergent in primary structure (e.g., the ligand binding domains of RARxcex1 and RXRxcex1 have only approximately 30% amino acid identity). These structural differences are reflected in the different relative degrees of responsiveness of RARs and RXRs to various vitamin A metabolites and synthetic retinoids. In addition, distinctly different patterns of tissue distribution are seen for RARs and RXRs. For example, RXRxcex1 mRNA is expressed at high levels in the visceral tissues, e.g., liver, kidney, lung, muscle and intestine, while RARxcex1 mRNA is not. Finally, the RARs and RXRs have different target gene specificity. In this regard, RARs and RXRs regulate transcription by binding to response elements in target genes that generally consist of two direct repeat half-sites of the consensus sequence AGGTCA. RAR:RXR heterodimers activate transcription ligand by binding to direct repeats spaced by five base pairs (a DR5) or by two base pairs (a DR2). However, RXR:RXR homodimers bind to a direct repeat with a spacing of one nucleotide (a DR1). See Mangelsdorf et al., xe2x80x9cThe Retinoid Receptorsxe2x80x9d in The Retinoids: Biology, Chemistry and Medicine, M. B. Sporn, A. B. Roberts and D. S. Goodman, Eds,. Raven Press, New York, N.Y., Second Addition (1994). For example, response elements have been identified in the cellular retinal binding protein type II (CRBPII), which consists of a DR1, and Apolipoprotein AI genes which confer responsiveness to RXR, but not RAR. Further, RAR has also been recently shown to repress RXR-mediated activation through the CRBPII RXR response element (Manglesdorf et al., Cell, 66:555-61 (1991)). Also, RAR specific target genes have recently been identified, including target genes specific for RARxcex2 (e.g., xcex2RE), which consists of a DR5. These data indicate that two retinoic acid responsive pathways are not simply redundant, but instead manifest a complex interplay.
RXR agonists in the context of an RXR:RXR homodimer display unique transcriptional activity in contrast to the activity of the same compounds through an RXR heterodimer. Activation of a RXR homodimer is a ligand dependent event, i.e., the RXR agonist must be present to bring about the activation of the RXR homodimer. In contrast, RXR working through a heterodimer (e.g., RXR:RAR, RXR:VDR) is often the silent partner, i.e., no RXR agonist will activate the RXR-containing heterodimer without the corresponding ligand for the heterodimeric partner. However, for other heterodimers, (.e., PPAR:RXR) a ligand for either or both of the heterodimeric partners can activate the heterodimeric complex. Furthermore, in some instances, the presence of both an RXR agonist and the agonist for the other heterodimeric partner (e.g., gemfibrizol for PPARxcex1 and TTNPB for RARxcex1) leads to at least an additive, and often a synergistic enhancement of the activation pathway of the other IR of the heterodimer pair (e.g., the PPARxcex1 pathway). See, e.g., PCT Aplication No. PCT/US93/10204, filed Oct. 22, 1993, published as PCT Publication No. WO 94/15902 on Jul. 21, 1994; R. Mukherjee et al., 51 J. Steroid Biochem. Molec. Biol., 157-166 (1994) and L. Jow and R. Mukherjee, 270 Journ. Biol. Chem., 3836-3840 (1995).
RAR and RXR retinoid agonists, including both RAR specific and RXR specific agonists have been previously identified. See e.g., PCT Publication Nos. WO 94/15902 WO93/21146, WO94/15901, WO94/12880, WO94/17796, WO94/20093, WO96/05165 and PCT Application No. PCT/US93/10166; EPO Patent Application Nos. 87110303.2, 87309681.2 and EP 0718285; U.S. Pat. Nos. 4,193,931, 4,539,134, 4,801,733, 4,831,052, 4,833,240, 4,874,747, 4,879,284, 4,898,864, 4,925,979, 5,004,730, 5,124,473, 5,198,567, 5,391,569 and Re 33,533; and H. Kagechika et al., xe2x80x9cRetinobenzoic Acids. 2. Structure-Activity Relationship of Chalcone-4-carboxylic Acids and Flavone-4xe2x80x2-carboxylic Acidsxe2x80x9d, 32 J. Med. Chem., 834 (1989); H. Kagechika et al., xe2x80x9cRetinobenzoic Acids. 3. Structure-Activity Relationships of Retinoidal Azobenzene-4-carboxylic Acids and Stilbene-4-carboxylic Acidsxe2x80x9d, 32 J. Med. Chem., 1098 (1989); H. Kagechika et al., xe2x80x9cRetinobenzoic Acids. 4. Conformation of Aromatic Amides with Retinoidal Activity. Importance of trans-Amide Structure for the Activityxe2x80x9d, 32 J. Med. Chem., 2292 (1989); M. Boehm et al., 37 J. Med. Chem., 2930 (1994); M. Boehm et al., 38 J. Med. Chem., 3146 (1995); E. Allegretto et al., 270 Journal of Biol. Chem., 23906 (1995); R. Bissonnette et al., 15 Mol. and Cellular Biol. 5576 (1995); R. Beard et al., 38 J. Med. Chem., 2820 (1995) and M. I. Dawson et al., xe2x80x9cEffect of Structural Modifications in the C7-C11 Region of the Retinoid Skeleton on Biological Activity in a Series of Aromatic Retinoidsxe2x80x9d, 32 J. Med. Chem., 1504 (1989). Further, antagonists to the RAR subfamily of receptors have recently been identified. See e.g., C. Apfel et al., 89 Proc. Natl. Acad. Sci., 7129 (1992); S. Keidel et al., 14 Mol. Cell Biol., 287 (1994); S. Kaneko et al., 1 Med. Chem. Res. 220 (1991); L. Eyrolles et al., 2 Med. Chem. Res. 361 (1992); J. Eyrolles et al., 37 J. Med. Chem., 1508 (1994); M-O Lee et al., 91 Proc. Natl. Acad. Sci., 5632 (1994); Yoshimura et al., 38 J. Med. Chem., 3163 (1995) and U.S. Pat. No. 5,391,766. In addition, various polyene compounds have been disclosed to be useful in the treatment of inflammatory conditions, psoriasis, allergic reactions, and for use in sunscreens in cosmetic preparations. See e.g., U.S. Pat. Nos. 4,534,979 and 5,320,833. Also, trienediolates of hexadienoic acids have proved useful in the synthesis of retinoic and nor-retinoic acids. See M. J. Aurell, et al., 49 Tetrahedron, 6089 (1993). However, to date, compounds that are RXR antagonist (e.g., that bind to RXR and do not activate, but antagonize transcription) and/or RXR selective compounds that have distinct heterodimer selective properties, such that they are capable of manifesting agonist, partial agonist and antagonist properties, have not been identified or characterized.
The present invention provides novel RXR modulators that selectively bind to RXR receptors in preference to RAR receptors and that, depending upon the receptor and/or cellular context, display activity as full agonists, partial agonists and/or full antagonists on RXR homodimers and/or RXR heterodimers. Thus, these compounds display unique selectivity for RXR heterodimers, and a referred to herein as dimer-selective RXR modulators. The present invention also provides pharmaceutical compositions incorporating these novel compounds and methods for the therapeutic use of such compounds and pharmaceutical compositions.
These and various other advantages and features of novelty which characterize the invention are pointed out with particularity in the claims annexed hereto and forming a part hereof. However, for a better understanding of the invention, its advantages, and objects obtained by its use, reference should be had to the accompanying drawings and descriptive matter, in which there is illustrated and described preferred embodiments of the invention.
In accordance with the present invention and as used herein, the following terms are defined with the following meanings, unless explicitly stated otherwise.
The term alkyl refers a straight-chain, branched-chain, cyclic and combination alkyls, including optional unsaturation (thereby resulting in alkenyls and alkynyls).
The term heteroalkyl refers to an optionally substituted straight-chain, branched-chain, cyclic and combination C1 to C10 alkyls containing one or more heteroatoms selected from the group consisting of halogen (i.e., F, Cl, Br, I) (including perfluoro alkyls), oxygen, nitrogen and sulfur, including optional unsaturation.
The term cycloalkyl refers to an optionally substituted C3 to C6 group which forms a ring, including optional unsaturation and optional heteroatom (e.g., O, N or S) substitution in or on the cyclalkyl ring.
The term aryl refers to optionally substituted phenyl, biphenyl, naphthyl or anthracenyl ring systems.
The term heteroaryl refers to an optionally substituted five-membered or six-membered heterocyclic or other aryl ring containing one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, including, without limitation, furyl, pyrrolyl, pyrrolidinyl, thienyl, pyridyl, piperidyl, indolyl, quinolyl, thiazole, benzthiazole and triazole.
The term arylalkyl or heteroarylalkyl refers to optionally substituted alkyls containing one or more aryl and/or heteroaryl groups.
The term acyl refers to alkyl, aryl or arylalkyl or heteroarylalkyl substitutes attached to a compound via a carbonyl functionality (e.g., xe2x80x94CO-alyl, xe2x80x94CO-aryl, xe2x80x94CO-arylalkyl or heteroarylalkyl etc. . .).
The term dimer-selective RXR modulator refers to a compound that binds to one or more Retinoid X Receptors and modulates (i.e., increases or decreases the transcriptional activity and/or biological properties of the given receptor dimer) the transcriptional activity of an RXR homodimer (i.e., RXR:RXR) and/or RXR in the context of a heterodimer, including but not limited to heterodimer formation with peroxisome proliferator activated receptors (e.g., RXR:PPARxcex1,xcex2,xcex31 or xcex32), thyroid receptors (e.g., RXR:TRxcex1 or xcex2), vitamin D receptors (e.g., RXR:VDR), retinoic acid receptors (e.g., RXR:RARxcex1,xcex2 or xcex3), NGFID receptors (e.g., RAR:NGFIB), NURR1 receptors (e.g., RXR:NURR1) LXR receptors (e.g., RXR:LZRxcex1,xcex2), DAX receptors (e.g., RXR:DAX), as well as other orphan receptors that form heterodimers with RXR, as either an agonist, partial agonist and/or antagonist. The particular effect of a dimer-selective RXR modulator as an agonist, partial agonist and/or antagonist will depend upon the cellular context as well as the heterodimer partner in which the modulator compounds acts. In this regard, the present invention describes dimer-selective RXR modulators, i.e., modulators that are selective activators and/or repressors through Retinoid X Receptors (i.e., RXRxcex1, RXRxcex2, and/or RXRxcex3) rather than Retinoic Acid Receptors (i.e., RARxcex1, RARxcex2, and/or RARxcex3).